Due to the ability of the macrocyclic molecules to coordinate with various metal cations, the discovery and synthesis of tetraazacycloalkane derivatives have attracted an increasing amount of attention for the past few years. Among them, cyclen (1,4,7,10-tetraazacyclododecane) and cyclam (1,4,8,11-tetraazacyclotetradecane) have been the focus of research, where it has been found that their macrocyclic molecular structure is very advantageous for forming metal complexes. Since such cyclic polyamines exhibit strong affinity to certain metal ions where they are capable of selectively binding with the metal ions, they can be used as metal catalysts, reaction sites for methalloenzyme, cleavers for phosphoric esters such as DNA and RNA, radioactive diagnosis and treatment, as well as MRI contrast agent, etc.
Among metal ions of high interest in the medical field, ions forming stable complexes with cyclen or cyclam derivatives include radioactive isotopes which can be used in nuclear medicine, as well as Gd which can be used as MRI contrast agent. 64Cu, 111In, 67Ga, 86Y, etc. are radioactive isotopes that can be used in diagnoses employing positron emission tomography (PET) or single photon emission computed tomography (SPECT), while 90Y is a radioactive isotope that can be used for therapy [Anderson C J, Welch M J. Radiometal-Labeled Agents (Non-Technetium) for Diagnostic Imaging. Chem. Rev. 1999, 99, 2219-2234; Anderson C J, Lewis J S. Radiopharmaceuticals for targeted radiotherapy of cancer. Expert Opinion on Therapeutic Patents 2000, 10, 1057-1069].
For instance, the use of radionuclides such as 64Cu in nuclear medicine or preclinical applications has been on the rise, and BFC is used to safely attach a radionuclide to a bioactive molecule, i.e. the target molecule. Thus, the development of BFC having excellent in vivo stability is very critical in designing a system for delivering a radionuclide in vivo.
A great deal of effort has been made to develop a ligand which is capable of chelating in a stable manner in vivo. The most common and general BFCs that has been studied are DOTA (1,4,7,10-tetraazacyclododecan-1,4,7,10-tetracetic acid) and TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetracetic acid). However, recent studies show that such generally used BFCs are rather unstable in vivo than the more recently developed BFCs such as cross-bridged tetraamine ligands and sarcophagine ligands due to the increased dissociation of metal.
Boswell et al. recently reported about cross-bridged cyclam derivatives for peptide conjugation and 64Cu radioactive labeling [C. Andrew Boswell. Celeste A. S. Regino, Kwamena E. Baidoo, Karen J. Wong, Ambika Bumb. Heng Xu, Diane E. Milenic, James A. Kelley. Christopher C. Lai. and Martin W. Brechbiel. Synthesis of a Cross-Bridged Cyclam Derivative for Peptide Conjugation and 64Cu Radiolabeling. Bioconjugate Chem. 2008, 19, 1476-1484]. They synthesized a 64Cu-cross-bridged(CB)-TE2A(1,8-bis-(carboxymethyl)-1,4,8,11-tetraazacyclotetradecane)-propeptide linker, and conjugated c[RGDfK(s)]. Furthermore, the Archibald group reported about NCSBz-CB-TE2A derivatives for bio-conjugation [Elizabeth A. Lewis, Ross W. Boyle and Stephen J. Archibald, Ultrastable complexes for in vivo use: a bifunctional chelator incorporating a cross-bridged macrocycle. Chem. Commun., 2004, 2212-2213]. However, the selective functionalization of nitrogen in cyclic polyamines is not obvious, and is still a difficult task in the organic synthesis field. For example, the synthesis of NCSBz-CB-TE2A involves 13 steps including the preparation of starting materials, and the overall yield of the final product is only 8.7%. Therefore, there is a need to design novel polyazamacrocyclic compounds that can be effectively used as BFCs, and to develop synthetic methods for preparing such compounds easily in a high yield.